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Published on: August 31, 2015
FOXP1 inhibits high glucose-induced ECM accumulation and oxidative stress in mesangial cells
Heli Xiang1, Wujun Xue1, Xiaoyan Wu2
1Department of Kidney Transplant, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
Abstract:
Diabetic nephropathy (DN) is a common complication of diabetes that remains the major cause of end-stage renal disease (ESRD). Forkhead box P1 (FOXP1) is a member of FOX family involved in the progression of diabetes. However, the pathogenic role of FOXP1 in DN remains unclear. This study was aimed to explore the effects of FOXP1 on glomerular mesangial cells (MCs) in response to high glucose (HG) stimulation. We found that HG stimulation markedly inhibited the FOXP1 expression in MCs in dose-and time-dependent manner. CCK-8 assay proved that FOXP1 overexpression attenuated HG-induced cell proliferation in MCs. FOXP1 exhibited anti-oxidative activity in HG-induced MCs, as proved by the decreased production of ROS and expressions of ROS producing enzymes, NADPH oxidase (NOX) 2 and NOX4. Besides, FOXP1 suppressed the expression and secretion of extracellular matrix (ECM) proteins including collagen IV (Col IV) and fibronectin (FN). Furthermore, FOXP1 overexpression significantly prevented HG-induced activation of Akt/mTOR signaling in MCs, and Akt activator blocked FOXP1-mediated cell proliferation, ROS production and ECM accumulation in MCs. Collectively, FOXP1 prevented HG-induced proliferation, oxidative stress, and ECM accumulation in MCs via inhibiting the activation of Akt/mTOR signaling pathway. The findings suggested that FOXP1 might be a therapeutic target for the treatment of DN.
Insights
Forkhead box P1 (FOXP1) protects kidney cells from high glucose damage by reducing oxidative stress and extracellular matrix buildup. This suggests FOXP1 is a potential therapeutic target for diabetic nephropathy.
Area of Science:
- Nephrology
- Molecular Biology
- Cell Biology
Background:
- Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD).
- The role of Forkhead box P1 (FOXP1) in DN pathogenesis is not well understood.
- Glomerular mesangial cells (MCs) are key players in DN progression.
Purpose of the Study:
- To investigate the effects of FOXP1 on MCs under high glucose (HG) conditions.
- To elucidate the molecular mechanisms underlying FOXP1's function in DN.
- To assess FOXP1's potential as a therapeutic target for DN.
Main Methods:
- Primary human MCs were treated with HG.
- FOXP1 expression was modulated (overexpression).
- Cell proliferation (CCK-8 assay), oxidative stress (ROS production, NOX enzyme expression), extracellular matrix (ECM) protein levels (Collagen IV, Fibronectin), and Akt/mTOR signaling pathway activation were assessed.
Main Results:
- HG inhibited FOXP1 expression in MCs.
- FOXP1 overexpression attenuated HG-induced MC proliferation.
- FOXP1 reduced HG-induced ROS production and NOX2/NOX4 expression.
- FOXP1 suppressed HG-induced Collagen IV and Fibronectin expression and secretion.
- FOXP1 inhibited HG-induced Akt/mTOR signaling activation.
- Akt activation reversed the protective effects of FOXP1.
Conclusions:
- FOXP1 protects MCs against HG-induced proliferation, oxidative stress, and ECM accumulation.
- These protective effects are mediated by the inhibition of the Akt/mTOR signaling pathway.
- FOXP1 represents a promising therapeutic target for DN treatment.
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